Supporting tumor suppression: The protein PTEN is a phosphatase and tumor suppressor whose activity is often decreased in human cancers. Thus, reactivating such a protein could potentially be an effective therapy against cancer. Lee et al. identified a ubiquitin E3 ligase (WWP1) as a PTEN-interacting protein that modifies PTEN and inhibits its tumor suppressive activity (see the Perspective by Parsons). Depletion of WWP1 increased dimerization and membrane recruitment of PTEN. A natural compound found to be a pharmacological inhibitor of WWP1 inhibited tumor growth in a mouse model of prostate cancer. Thus, reactivation of the tumor suppressor PTEN may provide a strategy for battling tumors. Science , this issue p. eaau0159 ; see also p. 633

BRAF plays an indispensable role in activating the MEK/ERK pathway to drive tumorigenesis. Receptor tyrosine kinase and RAS-mediated BRAF activation have been extensively characterized, however, it remains undefined how BRAF function is fine-tuned by stimuli other than growth factors. Here, we report that in response to proinflammatory cytokines, BRAF is subjected to lysine 27-linked poly-ubiquitination in melanoma cells by the ITCH ubiquitin E3 ligase. Lysine 27-linked ubiquitination of BRAF recruits PP2A to antagonize the S365 phosphorylation and disrupts the inhibitory interaction with 14–3–3, leading to sustained BRAF activation and subsequent elevation of the MEK/ERK signaling. Physiologically, proinflammatory cytokines activate ITCH to maintain BRAF activity and to promote proliferation and invasion of melanoma cells, whereas the ubiquitination-deficient BRAF mutant displays compromised kinase activity and reduced tumorigenicity. Collectively, our study reveals a pivotal role for ITCH-mediated BRAF ubiquitination in coordinating the signals between cytokines and the MAPK pathway activation in melanoma cells.

Concordant activation of MYC and BCL-2 oncoproteins in double-hit lymphoma (DHL) results in aggressive disease that is refractory to treatment. By integrating activity-based proteomic profiling and drug screens, polo-like kinase-1 (PLK1) was identified as an essential regulator of the MYC-dependent kinome in DHL. Notably, PLK1 was expressed at high levels in DHL, correlated with MYC expression and connoted poor outcome. Further, PLK1 signaling augmented MYC protein stability and, in turn, MYC directly induced PLK1 transcription, establishing a feed-forward MYC-PLK1 circuit in DHL. Finally, inhibition of PLK1 triggered degradation of MYC and of the anti-apoptotic protein MCL1, and PLK1 inhibitors showed synergy with BCL-2 antagonists in blocking DHL cell growth, survival and tumorigenicity, supporting clinical targeting of PLK1 in DHL.